The present invention relates to improved ophthalmic formulations, particularly to ophthalmic formulations for anti-inflammatory drugs, and specifically to an improved preservative system for ophthalmic formulations of carboxyl ("--COOH") group-containing drugs, especially non-steroidal anti-inflammatory drugs ("NSAIDs").
The invention also relates to methods of using these formulations for treating diseases that are either caused by, associated with or accompanied by inflammatory processes, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis, or any trauma caused by eye surgery or eye injury.
The topical use of NSAIDs, particularly pyrrolo pyrroles, in the treatment of ophthalmic diseases was first taught in U.S. Pat. No. 4,454,151, where NSAID compounds (such as those described in U.S. Pat. Nos. 4,089,969; 4,232,038; 4,087,539 and 4,097,579) were exemplified in formulation with NaH.sub.2 PO.sub.4.H.sub.2 O, Na.sub.2 HPO.sub.4.H.sub.2 O, NaCl, benzalkonium chloride ("BAC") and sterilized water. While the formulations described in the '151 patent were efficacious, a complex was found to form between the NSAID and the BAC. The formulations did not, therefore, have the stability desired for shelf life in commercial applications. A reasonable minimum shelf life is at least about one year, representing sufficient time to package, ship, and store a formulation without having to replace expired stock too frequently. Thus, the present invention entails an improvement over the formulations described in the '151 patent.
In general, an ophthalmic formulation contains an active compound and various ophthalmologically acceptable excipients, in the form of a solution, an ointment, a suspension, etc. An excipient is ophthalmologically acceptable if it is non-irritating to the eye and if its active ingredient penetrates the blood-aqueous barrier and/or difuses through the various ocular substructures to the site where it is pharmacologically active. The excipients can include a tonicifier, a preservative, a surfactant, a buffering system, a chelating agent, a viscosity agent as well as other stabilizing agents. Ophthalmic formulations must be sterile, and if intended for multiple dosing regimens, must be preserved with an effective anti-microbial agent.
Organo-mercurials (e.g., thimerosal, phenylmercuric acetate and phenylmercuric nitrate) have been used extensively as the preservative in ophthalmic solutions. These compounds, however, pose difficulties due to potential mercury toxicity as well as poor chemical stability. Benzalkonium chloride, a quaternary ammonium compound, has been widely used in ophthalmic solutions, and is considered to be the preservative of choice. However, BAC has typically been considered to be incompatible with anionic drugs (e.g., salicylates or nitrates, etc.) and can be inactivated by surfactants.
Many NSAIDs (such as ketorolac, indomethacin, flurbiprofen and suprofen) are being developed for ocular use because of their activity as anti-inflammatory agents as well as their ability to prevent cystoid macular edema.
These NSAIDs have proven to be incompatible with quaternary ammonium compounds such as BAC because they can form a complex with them, rendering the preservative less available to serve its function, as is the case with other ophthalmic drugs that contain a --COOH group. Thus, less preferred preservatives have been used in such ophthalmic formulations. For example, Ocufen Ophthalmic solution, the first NSAID (flurbiprofen) approved by the FDA for ophthalmic use, incorporates thimerosal (with EDTA) as its preservative system.
It has remained desired to provide a stable, clear, antimicrobially effective ophthalmic formulation for NSAIDs using BAC as the preservative, and an improved preservative system for --COOH group containing ophthalmic drugs.